JP2019131480A - Percutaneous absorption promoter and percutaneous preparation - Google Patents

Abstract

To provide a preparation that strikes a balance between skin permeability and low skin irritation.SOLUTION: A percutaneous absorption promoter contains at least a salt selected from the group consisting of choline-isostearic acid salt, guanidine-oleic acid salt and guanidine-isostearic acid salt, and tricaprylin.SELECTED DRAWING: Figure 1

Description

The present invention relates to absorbability (skin absorbability) when an active ingredient (substance exhibiting physiological activity) is absorbed through the skin of humans or other animals (transdermal absorption) in uses such as pharmaceuticals, cosmetics, and quasi drugs. Percutaneous absorption enhancer used for enhancing transdermal absorbability).
Furthermore, the present invention relates to a transdermal preparation containing such a transdermal absorption enhancer.

  As a method for administering a drug to a person, oral and injection are generally used, but in recent years, research and development on the skin is actively performed. The transdermal formulation has advantages over the oral formulation, such as avoiding a decrease in bioavailability due to the first-pass effect in the liver, and improving the compliance of elderly people and children with dysphagia. This is because it has advantages such as a reduction in invasiveness and a constant blood concentration of the drug over a long period of time.

  Patent Document 1 discloses an equimolar salt of a basic functional group-containing compound having a molecular weight of 50 to 120 and a melting point of 50 to 350 ° C., and an acidic functional group-containing compound having LogP of −4 to 7.3. It is disclosed that a transdermal absorption enhancer containing an ionic liquid is used to lower the barrier function of the stratum corneum of the skin, thereby increasing the penetration of the active ingredient into the skin.

Pamphlet of International Publication No. 2016/068336

The percutaneous absorption enhancer of Patent Document 1 provides a high skin permeation effect not only for poorly soluble active ingredients but also for water soluble active ingredients. However, obtaining a skin permeation effect of a drug using a percutaneous absorption enhancer weakens the barrier function of the skin, particularly the stratum corneum, and substantially damages the stratum corneum of the skin, It facilitates the penetration of substances from outside the body. Therefore, a percutaneous absorption enhancer that provides a high skin permeation effect is highly damaging to the skin and is likely to cause rough skin and rash.
On the other hand, when an absorption promoter with low irritation is used to reduce damage to the skin, the skin permeability of the drug is lowered and a sufficient healing effect cannot be obtained.
For this reason, it has been difficult to obtain a preparation having a balance between skin permeability and low skin irritation.

  As a result of intensive studies to solve the above-described problems, the present inventors have used various active ingredients (for example, acyclovir, mizoribine, methotrexate, oxycodone, lisinopril) when a specific salt that is an ionic liquid is used in combination with a specific compound. , Metformin, vildagliptin, tegafur, zoladex, alendronic acid, zoledronic acid and the like) and found that a percutaneous absorption preparation with low skin irritation can be obtained.

That is, the present invention is as follows.
[1] at least one salt selected from the group consisting of choline-isostearate, guanidine-oleate and guanidine-isostearate;
A transdermal absorption enhancer containing tricaprylin.
[2] at least one selected from the group consisting of choline-isostearic acid (1: 2) salt, guanidine-oleic acid (1: 1) salt and guanidine-isostearic acid (1: 1) salt;
A transdermal absorption enhancer containing tricaprylin.
[3] A transdermal preparation containing the percutaneous absorption enhancer according to [1] or [2] and an active ingredient.
[4] The transdermal preparation according to [3], wherein LogP of the active ingredient is 3.5 or less.
[5] A salt production step including at least one of the following steps (A) to (C):
Diluting the salt obtained in the above step with tricaprylin;
A method for producing a transdermal absorption enhancer.
(A): A step of mixing choline carbonate or bicarbonate and isostearic acid to produce choline-isostearate.
(B): A step of producing guanidine-oleate by mixing guanidine carbonate or bicarbonate and oleic acid.
(C): A step of producing guanidine-isostearate by mixing carbonate or bicarbonate of guanidine and isostearic acid.
[6] A step of producing a salt of a cation component and a fatty acid by mixing a carbonate or bicarbonate of the cation component and a fatty acid,
Diluting the salt obtained in the above step with tricaprylin;
A method for producing a transdermal absorption enhancer.

  According to the present invention, it is possible to provide a transdermal preparation having excellent transdermal absorbability and low skin irritation.

The diffraction profile converted from the X-ray-diffraction image obtained about Example a is shown.

  DESCRIPTION OF EMBODIMENTS Hereinafter, a mode for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described in detail. However, the present invention is not limited to this, and various modifications can be made without departing from the gist thereof. Is possible.

(1. Transdermal absorption enhancer)
First, the transdermal absorption enhancer of this embodiment will be described.
In the present embodiment, the “transdermal absorption enhancer” refers to a substance capable of improving the transdermal absorbability of the active ingredient by coexisting with the active ingredient.
The transdermal absorption enhancer of this embodiment contains one or more salts selected from the group consisting of choline-isostearate, guanidine-oleate, and guanidine-isostearate. These salts are usually ionic liquids that exist as liquids at room temperature (23 ° C.).
There is no limitation on the molar ratio of choline and isostearic acid, guanidine and oleic acid, or guanidine and isostearic acid in each salt. Choline-isostearic acid (1: 2) salt (salt having a molar ratio of choline and isostearic acid of 1: 2), guanidine-oleic acid (1: 1) salt (equimolar salt of guanidine and oleic acid), and And guanidine-isostearic acid (1: 1) salt (an equimolar salt of guanidine and isostearic acid).

The transdermal absorption enhancer of this embodiment further contains tricaprylin (also known as glyceryl tricaprylate, glycerin tricaprylate, 1,2,3-tri-n-octanoylglycerol) in combination with the above-mentioned salt.
According to the study by the present inventors, it was found that skin irritation can be reduced by using choline-isostearate, guanidine-oleate, and guanidine-isostearate diluted with tricaprylin. The reason is not clear, but it is presumed that the combination of these substances hardly dissolves the intercellular lipids in the stratum corneum. However, the mechanism does not depend on this.

  The compounding ratio of choline-isostearate, guanidine-oleate, and guanidine-isostearate and tricaprylin is not limited. For example, the mass ratio (salt: tricaprylin) is 0.1: 99.9. -50: 50, preferably 1: 99-50: 50, more preferably 1: 99-25: 75.

In the percutaneous absorption enhancer of this embodiment, if necessary, oils such as polyhydric alcohol, liquid paraffin, squalane, vegetable oil, higher fatty acid and higher alcohol, organic acids such as citric acid and lactic acid, surface activity It may contain other additives such as agents, pigments, dyes, preservatives, resins, pH adjusters, antioxidants, UV absorbers, chelating agents, thickeners, moisturizers, alcohol, water, and fragrances. it can.
However, since the surfactant has strong skin irritation, it is desirable that the surfactant is not included in the transdermal absorption enhancer of this embodiment.

(2. Transdermal formulation)
Next, the transdermal preparation of this embodiment will be described.
In this embodiment, the transdermal formulation refers to a formulation that absorbs (transdermally absorbs) the active ingredient through the skin of humans or other animals. For example, it is applied or affixed in the use of pharmaceuticals, cosmetics, and quasi drugs. In addition to patch preparations for percutaneously absorbing the active ingredient by means of, etc., it may be in the form of a poultice, emulsion, cream, lotion, essence, mousse, spray, gel, oil or the like.
In the case of a coating agent, by including the percutaneous absorption enhancer of this embodiment, the spreadability of the transdermal preparation is improved, and the effect of facilitating application to the skin can be expected.

The transdermal formulation of this embodiment contains the transdermal absorption enhancer of this embodiment and an active ingredient.
The active ingredient is not limited and can be widely applied to active ingredients such as pharmaceuticals, cosmetics, and quasi drugs.
The active ingredient may be either sparingly soluble or water-soluble. The transdermal absorption enhancer of the present embodiment has an effect of promoting transdermal absorption for both poorly soluble and water-soluble ones. It is also useful in that it exhibits an effect of promoting transdermal absorption. In that respect, in the transdermal preparation of this embodiment, it is effective to use a water-soluble active ingredient as an active ingredient.
Here, the water-soluble active ingredient means an active ingredient having a solubility in water at 20 ° C. of 0.5 mg / mL or more, preferably 10 mg / mL or more, more preferably 30 mg / mL or more. Particularly preferably, it is 100 mg / mL or more.

In the water-soluble active ingredient, the common logarithm LogP of the partition coefficient P between water and 1-octanol is preferably 3.5 or less, more preferably less than 2. Especially preferably, it is 0.5 or less.
When LogP is 0, the active ingredient is equally divided between water and 1-octanol. When LogP is 3.5 or less, the water solubility of the active ingredient is increased and the transdermal absorbability is lowered, so that the effect of the transdermal absorption enhancer of the present embodiment becomes more remarkable.
In the transdermal preparation of this embodiment, the water-soluble active ingredient may be in a salt state or in a free state that is not a salt.

  Here, LogP is a value generally used as an index of hydrophilicity / hydrophobicity of a compound, and is shaken by a flask shaking method ((1) water and 1-octanol are mixed for 24 hours or more. (2) 1-octanol / water (pH 7.4 buffer solution) obtained by shaking in a flask together with the substance to be measured (3) phase separation by centrifugation (4) quantifying the substance contained in each phase) Is the logarithm of the distribution coefficient actually measured at. LogP can also be obtained from the software “XLogP” (Shanghai Institute of Organic Chemistry, China Academy of Sciences, http: //www.sio-ccbg.ac.p Is listed in the database of PubChem (http://pubchem.ncbi.nlm.nih.gov/#) and can be used.

  Specifically, examples of water-soluble active ingredients used in pharmaceuticals include antipyretic analgesic / anti-inflammatory drugs (acetaminophen, LogP = 0.5, aspirin, LogP = 1.2, isopropylantipyrine, LogP = 1.7, etc. ), Opioid analgesics (oxycodone, LogP = 1.2, morphine, LogP = 0.8, remifentanil, LogP = 1.9, pethidine, LogP = 2.5, pentazocine, LogP = 3.3, butorphanol, LogP = 3.8, tramadol, LogP = 2.6, naloxone, LogP = 2.1, hydrocodone, logP = 2.2, etc., hypnotic sedative (chloral hydrate, LogP = 1, bromvalerylurea, LogP = 1) .1 etc.), sleepiness prevention drug (caffeine, LogP = -0.1 etc.), antipruritic drug, steroid (predniso , LogP = 1.6, methylprednisolone, LogP = 1.9, betamethasone, LogP = 1.9,), pediatric analgesics, stomachic medicine (hyoscyamine, LogP = 1.7, ethyl aminobenzoate, LogP = 1.9, etc.), antacid (famotidine, LogP = −0.6, ranitidine, LogP = 0.3, cimetidine, LogP = 0.4, lafutidine, LogP = 1.4, nizatidine, LogP = 1.6 Omeprazole, LogP = 2.2, esomeprazole, LogP = 2.2, lansoprazole, LogP = 2.8, etc.) and digestive drugs.

  In addition, cardiotonic drugs (dopamine, LogP = -1, methylxanthine, LogP = -0.7, isoprenaline, LogP = -0.6, amrinone, LogP = -0.2, milnoline, LogP = 0, digoxin, LogP = 1.3, Denopamine, LogP = 1.8, Methyldigoxin, LogP = 1.8, Digitoxin, LogP = 2.3, Vesnarinone, LogP = 2.1, Docarpamine, LogP = 2.9, etc.), Arrhythmic drug (ATP, LogP = −5.7, sotalol, LogP = 0.2, atenolol, LogP = 0.2, procainamide, LogP = 0.9, nifekalant, LogP = 1.1, bisoprolol, LogP = 1.9. , Mexiletine, LogP = 2.1, lidocaine, LogP = 2.3, pilsicainide, LogP = 2. Etc.), antihypertensive drug (lisinopril, LogP = -2.9, methyldopa, LogP = -1.9, imidapril, LogP = -0.7, enalapril, LogP = -0.1, captopril, LogP = 0.3, Cilazapril, LogP = 0.6, Perindopril, LogP = 0.9, Temocapril, LogP = 1, Quinapril, LogP = 1.2, Benazepril, LogP = 1.3, Terazosin, LogP = 1.4, Urapidil, LogP = 1.5, clonidine, LogP = 1.6, delapril, LogP = 1.7, prazosin, LogP = 2, trandolapril, LogP = 2, guanfacine, LogP = 2, alacepril, LogP = 2.1, bunazosin, LogP = 2.2, nifedipine, LogP = 2.2, arotinolol, LogP = .3, doxazosin, LogP = 2.5, phentolamine, LogP = 2.6, tolazoline, LogP = 2.6, amlodipine, LogP = 3, bevantolol, LogP = 3), vasodilator (hydralazine, LogP = 0. 7, Loniten, LogP = 1.2, pen slit, LogP = 1.4, etc.), diuretic (isosorbide, LogP = -1.4, acetazolamide, LogP = -0.3, hydrochlorothiazide, LogP = -0.1 , Methiclan, LogP = 0.5, trichloromethiazide, LogP = 0.6, chlorthalidone, LogP = 0.9, mesulfide, LogP = 0.9, triamterene, LogP = 1, eplerenone, LogP = 1.4, furosemide , LogP = 2, torasemide, LogP = 2.7, etc.).

  In addition, anti-ulcer drugs (pirenzepine, LogP = 0.1, butylscopolamine bromide, LogP = 0.9, rebamipide, LogP = 2.4, etc.), intestinal drugs (guaiacol, LogP = 1.3, etc.), osteoporosis Therapeutic (Paratormon, LogP = −18.7, Ercitonin, LogP = −13.3, Alendronate, LogP = −6.5, Risedronate, LogP = −3.5, Etidronate, LogP = −3.7 Etc.), anti-rheumatic drugs (mizoribine, LogP = -1.9, D-penicillamine, LogP = -1.8, methotrexate, LogP = -1.8, actarit, LogP = 0.4, epilysole, LogP = 1. 3. Leflunomide, LogP = 2.6, Tacrolimus, LogP = 2.7) Antitussive expectorant, anti-asthma, antibacterial, frequent urination Nourishing tonic, and the like vitamins.

  Examples of water-soluble active ingredients used in cosmetics and quasi drugs include whitening agents, anti-aging agents, antioxidants, moisturizers, hair restorers, cell activators, vitamins, amino acids and the like. Specifically, arbutin (LogP = −0.6), L-ascorbic acid (LogP = −1.6), hydroquinone (LogP = −0.6), glutathione (LogP = −4.5), placenta extraction , Pantothenic acid (LogP = -1.1), tranexamic acid (LogP = -2), kojic acid (LogP = -0.9), L-cysteine (LogP = -2.5), ellagic acid (LogP = 1.1), lucinol (LogP = 2.4), resorcin (LogP = 0.8), astaxanthin and its derivatives, rutin (LogP = -1.3), cholesterol and its derivatives, tryptophan (LogP = -1. 1), flavonoids such as histidine (LogP = -3.2), quercetin (LogP = 1.5) and quercitrin (LogP = 0.9), (LogP = 0.4) and derivatives thereof, gallic acid (LogP = 0.7) and derivatives thereof, kinetin (LogP = 1), α-lipoic acid (LogP = 1.7), erythorbic acid (LogP = −) 1.6) and derivatives thereof, thiotaurine (LogP = −0.1), urea (LogP = −1.4), nicotine (LogP = 1.2) and derivatives thereof, nicotinic acid (LogP = 0.4), Hydroxyproline (LogP = -3.3), Serine (LogP = -3.1), Glutamic acid (LogP = -3.7), Arginine (LogP = -4.2), Alanine (LogP = -3), Minoxidil (LogP = 1.2), D-glucosamine (LogP = -2.8), N-acetyl-D-glucosamine (LogP = -1.7), hyaluronic acid (LogP = -7.4) , Raffinose (LogP = −5.8), azelaic acid (LogP = 1.6), γ-aminobutyric acid (LogP = -3.2), allantoin (LogP = −2.2), L-carnitine (LogP = -0.2) and biotin (LogP = 0.3).

  As active ingredients that can be included in the transdermal preparation of this embodiment, minodronic acid (LogP = −2.2), risedronic acid (LogP = −3.1), ibandronic acid (LogP = −4.1) ), Zoledronic acid (LogP = -4.3), alendronic acid (LogP = -6.5), vildagliptin (Equa) (LogP = 0.9), metformin (LogP = -1.3), pregabalin (LogP) = -1.6), gabapentin (LogP = -1.1), mirogabalin (LogP = -1.7), baclofen (LogP = -1), tegafur (LogP = -0.3), capecitabine (LogP = 0) .6), pemetrexed (LogP = 0.2), levodopa (LogP = -2.7), carbidopa (LogP = -2.2), benserazide (LogP = 1.3), droxidopa (LogP = -3.2), and the like can be mentioned Torerifu (LogP = 0.9).

  In the present embodiment, the content of the active ingredient in the transdermal preparation is not limited. However, the active ingredient is present in excess of the solubility in the transdermal absorption enhancer so that the active ingredient contained in the transdermal preparation does not deplete after the skin permeation. It is preferable. The cycle in which the active ingredient existing in the non-dissolved state is sequentially dissolved in the percutaneous absorption enhancer and permeated through the skin is repeated, so that the total skin permeation amount can be increased.

In the present embodiment, the content of the transdermal absorption enhancer in the transdermal preparation is not limited, but the content of the transdermal absorption enhancer in the present embodiment is 1 to 99.9% by mass. preferable.
If content of the percutaneous absorption enhancer of this embodiment is 1 mass% or more, the percutaneous absorbability improvement effect will fully be exhibited. More preferably, it should be equimolar or more with respect to the water-soluble active ingredient, and can be increased or decreased in view of the effect. On the other hand, if the content of the transdermal absorption enhancer of this embodiment is 99.9% by mass or less, sufficient efficacy of the active ingredient can be obtained.

  Furthermore, in this embodiment, the transdermal preparation can also contain other transdermal absorption enhancers as required in addition to the transdermal absorption enhancer of this embodiment. The amount of the other transdermal absorption enhancer may be, for example, 0.01 to 10 times the amount of the water-soluble active ingredient on a mass basis.

In the transdermal preparation of this embodiment, if necessary, polyhydric alcohol, liquid paraffin, squalane, vegetable oil, higher fatty acid, oil such as higher alcohol, organic acids such as citric acid and lactic acid, surfactants, etc. , Pigments, dyes, preservatives, resins, pH adjusters, antioxidants, ultraviolet absorbers, chelating agents, thickeners, humectants, alcohol, water, fragrances and the like.
However, since the surfactant has strong skin irritation, it is desirable that the surfactant is not included in the transdermal preparation of this embodiment.

  When the transdermal preparation is a patch (patch preparation) that percutaneously absorbs the active ingredient by sticking or the like, a layer containing the transdermal preparation can be laminated on the support. In this case, an adhesive layer may be further provided on the layer containing the transdermal preparation, or an adhesive may be added to the layer containing the transdermal preparation. Examples of adhesives include acrylic adhesives, natural rubber adhesives, synthetic rubber adhesives, silicone adhesives, vinyl ester adhesives, vinyl ether adhesives, etc., skin irritation, skin contact, etc. Those that can be easily controlled are preferred. These may be used alone or in combination of two or more. Two or more kinds may be laminated and used. Further, it may contain a softener, a filler, an antioxidant and the like.

  Examples of the synthetic rubber adhesive include polyisobutylene, polyisoprene, styrene-butadiene rubber, styrene-isoprene-styrene copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-butadiene rubber-styrene block copolymer. Examples thereof include coalescence, polybutene, butyl rubber, and silicon rubber. As an acrylic adhesive, acrylic acid alkyl ester, polymethacrylic acid alkyl ester, etc. are mentioned, for example.

(3. Method for producing transdermal absorption enhancer)
In this embodiment, the percutaneous absorption enhancer is produced by mixing a carbonate or bicarbonate of a cation component and a fatty acid to produce a salt of the cation component and the fatty acid, and diluting this with tricaprylin. Is preferred. According to the studies by the present inventors, when a cation component-fatty acid salt is produced by mixing a carbonate or bicarbonate of a cation component and a fatty acid, a salt with little change over time can be obtained, and this is used. It was also found that a transdermal absorption enhancer that is particularly superior in skin irritation than when using a salt obtained by another method can be produced.

Here, when mixing the carbonate or bicarbonate of the cation component and the fatty acid, both may be mixed as they are, or the carbonate or bicarbonate of the cation component and the fatty acid, either or either, any Both may be mixed after dissolving in a solvent to form a solution. For example, the carbonate or bicarbonate of the cation component is dissolved in water, an alcohol solvent such as ethanol or an aqueous alcohol solution, the fatty acid is dissolved in an alcohol solvent such as ethanol, and the resulting solution is mixed to obtain a carbonate of the cation component. Salts or bicarbonates and fatty acids can be mixed. The concentration of the solution at this time is not limited, but may be 0.01 to 6 mol / L, for example.
There is no limitation on the mixing method, and the other may be added little by little to one solution, or both may be mixed simultaneously. There is no limitation also on mixing temperature, for example, room temperature (25 degreeC) or less may be sufficient, and you may heat suitably.
The obtained cation component-fatty acid salt (ionic liquid) can be separated by distilling off the solvent by distillation or the like.

In this embodiment, the manufacturing process of the salt of a cation component and a fatty acid can include at least one of the following (A) to (C) in more detail.
(A): A step of mixing choline carbonate or bicarbonate and isostearic acid to produce choline-isostearate.
(B): A step of producing guanidine-oleate by mixing guanidine carbonate or bicarbonate and oleic acid.
(C): A step of producing guanidine-isostearate by mixing carbonate or bicarbonate of guanidine and isostearic acid.

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, these are not intending limiting the range of this invention to an Example.
<Synthesis of salt used in the present invention>
The salt used in the present invention was prepared as follows.
1. Production Example 1
Production of choline-isostearic acid (1: 2) salt (derived from choline bicarbonate) 18.0 g (0.080 mol) of choline bicarbonate (80% by weight aqueous solution) was added to 100 mL of ethanol, placed in an eggplant type flask, and stirred with a stirrer. Further, a solution obtained by further dissolving 45.5 g (0.160 mol) of isostearic acid in 100 mL of ethanol was added dropwise and mixed at room temperature. Using a rotary evaporator, the solvent was distilled off under reduced pressure in a 40 ° C. water bath. After the solvent was removed, the mixture was further dried under reduced pressure at 40 ° C. for 14 hours to obtain choline-isostearate (1: 2) was obtained.
The obtained choline-isostearic acid (1: 2) salt was a colorless and transparent liquid at room temperature.
The pH of the obtained choline-isostearic acid (1: 2) salt was 7.1 when measured using an ISFET electrode (model: 0040-10D, manufactured by Horiba, Ltd.). Furthermore, when the pH of the sample was measured after storage at 4 ° C. for 1 month, it was 7.2.

2. Production Example 2
Production of choline-isostearic acid (1: 2) salt (derived from choline hydroxide) 19.4 g (0.080 mol) of choline hydroxide (50% by mass aqueous solution) was added to 100 mL of ethanol, placed in an eggplant type flask, and stirred with a stirrer. Further, a solution obtained by further dissolving 45.5 g (0.160 mol) of isostearic acid in 100 mL of ethanol was added dropwise and mixed at room temperature. Using a rotary evaporator, the solvent was distilled off under reduced pressure in a 40 ° C. water bath. After the solvent was removed, the mixture was further dried under reduced pressure at 40 ° C. for 14 hours to obtain choline-isostearate (1: 2) was obtained.
The obtained choline-isostearic acid (1: 2) salt was a colorless to slightly yellowish transparent liquid at room temperature.
The pH of the obtained choline-isostearic acid (1: 2) salt was 7.6 when measured using an ISFET electrode (model: 0040-10D, manufactured by Horiba, Ltd.). Furthermore, when the pH of the same sample was measured after storage at 4 ° C. for 1 month, it was 9.1, and an increase in pH was observed.

3. Production Example 3
Manufacture of guanidine-oleic acid (1: 1) salt (derived from guanidine carbonate) 100 mL of pure water was dissolved in 7.2 g (0.040 mmol) of guanidine carbonate, dissolved in 100 mL of ethanol, placed in an eggplant-shaped flask, and stirred with a stirrer. While stirring, a solution of 14.4 g (0.080 mol) of oleic acid dissolved in 100 mL of ethanol was added dropwise at room temperature and mixed. Using the rotary evaporator, the solvent was distilled off under reduced pressure in a 40 ° C. water bath using a rotary evaporator. After the solvent disappeared, the mixture was further dried under reduced pressure at 40 ° C. for 14 hours to obtain guanidine-oleate (1: 1) was obtained.
The obtained guanidine-oleate was a white gel at room temperature.
When the pH of the obtained guanidine-oleate (1: 1) salt was measured using an ISFET electrode (model: 0040-10D, manufactured by Horiba, Ltd.), it was 7.4. Furthermore, when the pH of the sample was measured after storage at 4 ° C. for 1 month, it was 7.6.

4). Production Example 4
Manufacture of guanidine-isostearic acid (1: 1) salt (derived from guanidine carbonate) Dissolve 100 mL of pure water in 7.2 g (0.040 mmol) of guanidine carbonate, add it to 100 mL of ethanol, and add to a eggplant-shaped flask. While stirring, a solution of 22.7 g (0.080 mol) of isostearic acid dissolved in 100 mL of ethanol was added dropwise at room temperature and mixed. Using a rotary evaporator, the solvent was distilled off under reduced pressure in a 40 ° C. water bath. After the solvent was removed, the mixture was further dried under reduced pressure at 40 ° C. for 14 hours to obtain guanidine-isostearic acid (1: 1 )
The obtained guanidine-oleate was a white gel at room temperature.
When the pH of the obtained guanidine-isostearic acid (1: 1) salt was measured using an ISFET electrode (model: 0040-10D, manufactured by Horiba, Ltd.), it was 7.7. Further, the pH of the sample measured after storage at 4 ° C. for 1 month was 7.8.

<Evaluation of skin irritation of transdermal absorption enhancer (1)>
In the combinations shown in Table 1, the salts obtained in Production Examples 1 to 4, or laurocapram or limonene (20% by mass) used in existing percutaneous absorption enhancers, and a diluent (2-octyldodecanol) Or tricaprylin) (80 mass%) was mixed, and the transdermal absorption promoter of Examples 1-4 and Comparative Examples 1-5 was prepared. About these, skin irritation was evaluated by the following method.
For white guinea pig females, after shaving and shaving the left and right side torso, apply 0.2 mL of a transdermal absorption enhancer to a 2 × 2 cm patch (lint cloth), and then to the left and right side torso The film was affixed to and fixed with a polyethylene film tape. The patch was removed 6 hours after administration, and the administration site was wiped with absorbent cotton moistened with ethanol. The administration site was observed 24 hours after the patch was removed, and the presence or absence of skin reactions such as erythema and edema was observed. The results are shown in Table 1. The percutaneous absorption enhancer using the salt selected in the present invention and using tricaprylin as a diluent showed no skin reaction or even if it was shown, the skin irritation could be suppressed.

<Evaluation of skin irritation of transdermal absorption enhancer (2)>
The effect of the percutaneous absorption enhancer of the present invention on the skin structure (long-period lamella structure and hydrocarbon chain filling structure of the stratum corneum) was evaluated by small-angle and wide-angle diffraction experiments using high-intensity X-rays. For the measurement, a BL19B2 beam line of SPring-8 was used, and the method described in the following document 1 was used as a reference.
Reference 1: Chemistry and Physics of Lipids, Volume 163, Issues 4-5, 2010, pages 381-389 Specifically, the skin stratum corneum of hairless mice is disturbed so as not to have orientation in the solution cell. The transdermal absorption enhancer prepared by mixing the salt or laurocapram and tricaprylin produced in Production Examples 1 to 3 at 15:85 (w / w) was injected into the cell, and the transdermal absorption enhancer was added 150 immediately after the start of injection. X-ray diffraction images were taken for a minute.
The hairless mouse skin stratum corneum is prepared by washing and drying the skin stratum corneum peeled from the frozen hairless mouse skin (product name: Labskin, Hoshino Test Animal Breeding) by trypsin treatment, and adjusting the moisture to about 20%. used.
The imaging conditions for the X-ray diffraction image are as follows.
X-ray wavelength: 0.069 nm (18 keV)
Camera length: 768mm
Beam diameter φ: 300 μm
Beam stopper φ: 3mm
Large pixel detector: PILATUS 2M
Exposure time: 30 seconds Shooting interval: 30 seconds

The obtained X-ray diffraction image is converted into a one-dimensional diffraction profile, and a secondary reflection peak derived from the long-period lamellar structure of the skin stratum corneum (Peaak A, S = 0.15 nm ⁻¹ in FIG. 1) ) And the peak of the peak derived from the hydrocarbon chain packing structure (Peak B in FIG. 1, S = 2.4 nm ⁻¹ vicinity) is obtained by fitting with a Gaussian function. The area ratio after 1 minute after application of the skin absorbent to the stratum corneum and 30 minutes after application was evaluated.

Peak A peak area ratio is (the peak area 30 minutes after applying the transdermal absorption enhancer to the stratum corneum) ÷ (applying the transdermal absorption enhancer to the stratum corneum) for the secondary reflection peak derived from the long-period lamellar structure (The peak area after 1 minute).
Peak B peak area ratio is (peak area 30 minutes after applying the transdermal absorption enhancer to the stratum corneum) / (1 after applying the transdermal absorption enhancer to the stratum corneum) for the peak derived from the hydrocarbon chain packing structure. Min peak area).
The results are shown in Table 2. In addition, the said area ratio shows that the corresponding skin structure melt | dissolved with the percutaneous absorption enhancer, so that the value is small.

  When the percutaneous absorbent of Comparative Example a is used, the area ratio of Peak A derived from the long-period lamella structure to Peak B of the hydrocarbon chain-filled structure uses the transdermal absorbent of Examples a to c. The value was smaller than the case. That is, it was confirmed that the percutaneous absorption enhancers of Examples a to c had less influence on the skin than the percutaneous absorption enhancer of Comparative Example a.

<Evaluation of skin permeability of transdermal preparation>
The active ingredient (drug), tricaprylin, and the salts obtained in Production Examples 1 to 4, or laurocapram or limonene used in existing percutaneous absorption enhancers are weighed so as to have the composition shown in Table 2. Taken into a test tube, kneaded until uniform using a spoon, mixed with ultrasonic waves for 1 hour, and allowed to stand for 12 to 18 hours to obtain a transdermal preparation. The obtained preparation was subjected to the whole Franz cell test.

The Franz cell test was performed under the following conditions.
Device name: Microette Plus, Hanson Research vertical diffusion cell; 7 mL, model 58-001-457
Hairless mouse skin; Lab skin, Hoshino test animal farm, soaked in water at room temperature for 15 minutes and used after thawing. Receptor solution: PBS (−), manufactured by Wako Pure Chemical Industries, Ltd.
Temperature (set value): 32.5 ° C
Effective area of the membrane; 0.75 cm × 1.75 cm × 3.14 = 1.766 cm ² ,
Sampling time: 0.5, 1, 1.5, 2, 4, 8, 12, 18, 24 hours Sampling method: At each sampling time, 1.5 ml of buffer solution is injected into the diffusion cell from near the bottom, and from the top of the cell. The liquid to be extruded was collected as a sampling liquid. In addition, injection of the buffer solution at the time of sampling was performed twice, and the solution sampled at the second time was collected as a sampling solution for API concentration measurement.

Quantification of each active ingredient (API) was performed by high performance liquid chromatography, and the 24 h cumulative skin permeation amount of API was determined using the following formula, and this was divided by the API charge amount to obtain the 24 h cumulative permeation rate.
Cumulative skin penetration [μg] = CnV + Σ (i = 1, n−1) CiS)
Cn: drug concentration [μg / mL] sampled at the nth (n is the number of samplings performed in 24 hours (9 times this time))
V: Franz cell capacity [mL]
Σ (i = 1, n−1) Ci: total drug concentration from the first sampling to the n−1th sampling (n is the number of samplings performed in 24 hours (9 times this time)) [μg / mL]
S: Volume of sampled liquid [mL]

The results are shown in Table 3. In the preparations of Examples, compared with the preparations using the existing percutaneous absorption enhancers (laurocapram, limonene), the cumulative skin permeation rate of 24 h or more was shown with the addition of a small amount of percutaneous absorption enhancers.

  The transdermal absorption enhancer of the present invention can be used in applications such as pharmaceuticals, cosmetics, and quasi drugs.

Claims (6)

At least one salt selected from the group consisting of choline-isostearate, guanidine-oleate and guanidine-isostearate;
A transdermal absorption enhancer containing tricaprylin. At least one selected from the group consisting of choline-isostearic acid (1: 2) salt, guanidine-oleic acid (1: 1) salt and guanidine-isostearic acid (1: 1) salt;
A transdermal absorption enhancer containing tricaprylin.   A transdermal preparation comprising the percutaneous absorption enhancer according to claim 1 or 2 and an active ingredient.   The transdermal preparation according to claim 3, wherein LogP of the active ingredient is 3.5 or less. A salt production step including at least one of the following steps (A) to (C):
Diluting the salt obtained in the above step with tricaprylin;
A method for producing a transdermal absorption enhancer.
(A): A step of mixing choline carbonate or bicarbonate and isostearic acid to produce choline-isostearate.
(B): A step of producing guanidine-oleate by mixing guanidine carbonate or bicarbonate and oleic acid.
(C): A step of producing guanidine-isostearate by mixing carbonate or bicarbonate of guanidine and isostearic acid. A step of producing a salt of a cation component and a fatty acid by mixing a carbonate or bicarbonate of the cation component and a fatty acid,
Diluting the salt obtained in the above step with tricaprylin;
A method for producing a transdermal absorption enhancer.